Modification of methadone synthesis process step

ABSTRACT

Alkylation of diphenylacetonitrile in methadone synthesis is carried out in presence of sodium hydroxide and DMF.

BACKGROUND OF THE INVENTION

Methadone, 6-dimethylamino-4,4-diphenyl-3-heptanone, is a syntheticnarcotic analgesic developed during World War II by the German chemists,Bockmuhl and Ehrhart, Ann., 561,52 (1948). The synthesis of methandoneby their procedure begins with the reaction of diphenylacetonitrile and1-dimethylamino-2-chloropropane in the presence of sodamide. A highyield of alkylation products is obtained comprising a mixture of twoisomeric alkylated diphenylacetonitriles in approximately equal amounts.The nitriles are respectively (I)2,2-diphenyl-4-dimethylaminovaleronitrile (mp 91°-92° C.) and (II)2,2-diphenyl-3-methyl-4-dimethylaminobutyronitrile (mp 69°-70° C.). Thehigh melting nitrile, upon reaction with ethyl magnesium bromide andsubsequent hydrolysis, yields methadone. The low melting nitrile reactswith ethyl magnesium bromide to give a stable ketimine,3-imino-4,4-diphenyl-5-methyl-6-dimethylaminohexane, which is hydrolyzedwith difficulty to the ketone, isomethadone.

The production of these two isomeric nitriles in a single reaction isexplained as follows: In the course of the reaction,1-dimethylamino-2-chloropropane cyclizes to yield1,1,2-trimethylaziridinium chloride of the following structure: ##STR1##

The aziridinium ring is quite unstable and reacts with thediphenylacetonitrile anion (produced under basic conditions) to yieldthe mixture of isomeric alkylated nitriles set forth above. When theaziridinium ring opens with a breaking of the bond marked with a smalla, the desired nitrile I is produced while the rupture of theaziridinium bond marked with a small b yields the isomeric nitrile.Naturally since, on further reaction, nitrile I yields methadone and thenitrile II yields isomethadone, not a useful analgesic, it has beenthought desirable to maximize the yields of the desired nitrile I byfinding reaction conditions which favored the rupturing of theaziridinium ring at bond a. Many experiments, however, using differentsolvents, temperatures, etc. yielded, within experimental error, thesame ratio of nitrile I and nitrile II, thus leading to the conclusionthat the ring opening reaction was a first order reaction and thusindependent of environment.

The methadone literature is too voluminous to be reviewed, but the abovechemistry is set forth in one or more of the following publications:Schultz et al., J. Am. Chem. Soc., 69, 188,2454 (1947), Cheney et al.,ibid, 71, 53, (1949); Easton et al., ibid, 69,2941 (1947), M. M. Baizer,Bull. on Narcotics, U.N. 5 (1), 32 (1953) (a review article). Methadoneis referred to as amidon in some of the above publications.

The only reference to a procedure other than the sodamide-toluene ort-butoxide--t-butanol solvent procedures of the above references for thealkylation of diphenylacetonitrile is Cusic, J. Am. Chem. Soc., 71, 3546(1949). Cusic employed a melt with 1-dimethylamino-2-chloropropane,diphenylacetonitrile and sodium hydroxide in the absence of a solvent.In my hands, both the Cusic and Bockmuhl procedures yield at best a 6:4isomer ratio of the desired isomer to the undesired (isomethandoneintermediate) isomer.

It is an object of this invention to provide an alkylation step in aprocedure for the preparation of methadone involving the reaction of1-dimethylamino-2-chloropropane and diphenylacetonitrile such that theratio of the desired to undesired isomer is greater than 6:4.

SUMMARY OF THE INVENTION

In accordance with the above and other objects, this invention providesa process whereby 1-dimethylamino-2-chloropropane is reacted withdiphenylacetonitrile in the presence of sodium hydroxide in a polar,aprotic solvent. The product of this reaction is a mixture of2,2-diphenyl-4-dimethylaminovaleronitrile and2,2-diphenyl-3-methyl4-dimethylaminobutyronitrile in better tha a 6:4ratio. My novel process is carried out as follows: About a 50-100% molarexcess of solid sodium hydroxide is ground to a fine powder and thepowder added to a polar, aprotic solvent such as dimethylformamide in,for example, a 1:8 w/v ratio. A solution of diphenylacetonitrile in thesame solvent in about a 1:1 or 1:2 w/v ratio is added thereto. Afterstirring this reaction mixture briefly in order to assure completeformation of the sodium salt of diphenylacetonitrile, a solution of1-dimethylamino-2-chlorpropane free base is added in increments. Thereaction is exothermic and the rate of addition of the free base is suchthat the reaction temperature can readily be controlled with the coolingmeans available. The reaction mixture is then heated to about 50° C. fora period of from 1 to 2 hours. The reaction mixture is next cooled,diluted with water, and the resulting suspension extracted several timeswith a water immiscible solvent, preferably benzene. The organicextracts are combined, washed with water and with saturated sodiumchloride and are then dried. Removal of the solvent in vacuo yields acrude product which contains 2,2-diphenyl-4-dimethylaminovaleronitrileand 2,2-diphenyl-3-methyl-4-dimethylaminobutyronitrile in a 2:1 ratio orbetter as determined by vapor phase chromatography. The isomer mixtureis about 90-98 percent of the total weight of isolated product, theremainder being recovered diphenylacetonitrile. The isomer mixture isseparated into its component parts by standard procedures such ascrystallization from hexane or by chromatography using, for example,silica gel and a benzene-methanol 8:2 solvent mixture as the elutingsolvent.

In the above reaction, the reactant concentrations do not affect theisomer ratio, but they do affect the amount of desired isomer obtainedin pure state. Obviously, the more complete the reaction ofdiphenylacetonitrile, the less of that starting material will be presentin the nitrile isomer mixture to hinder separation and purification ofthe separated isomers. We, therefore, prefer to employ a 50-100 percentexcess of base and a 10-20 percent excess of1-dimethyamino-2-chloropropane.

The temperature of the reaction also does not materially influence theisomer ratio but is important to the completeness of the reaction.Temperatures from 35-100 degrees C. are fully operative, but I prefer tocarry out my novel reactions at a temperature of about 75° C. with arange of 5° C. (70°-80° C.) being consistent with virtually completereaction of the diphenylacetonitrile and minimal quantities ofby-products.

As previously stated, a polar, aprotic solvent should be used in theabove process step. I have found that polar, aprotic solvents having adi-electric constant higher than 28 (when determined at 25° C.) aresuitable solvents for the above reaction. Such solvents includedimethylformamide (DMF) ε₂₅° 32 36.71, dimethylacetamide (DMAC) ε₂₅° 3237.8, dimethylsulfoxide (DMSO), ε₂₅° 32 45 and other similar solventsincluding nitrobenzene, N-methyl formamide and hexamethylphosphoramide.It is also important that the polar, aprotic solvent employed as areaction medium be inert; i.e., not contain any groups which might reacteither with sodium hydroxide, with chlorpropylamine or with itsaziridinium halide intermediate form.

This invention is further illustrated by the following specificexamples.

EXAMPLE 1

Following the procedure of Schultz and Sprague, J. Am. Chem. Soc., 70,48 (1948), a solution containing 3.77 g. of 1-dimethylamino-2-propanoland 10 ml. of chloroform was cooled with stirring to a temperature ofabout 0° C. A solution of 5.72 g. of freshly distilled thionylchloridein 2 ml. of chloroform was added thereto. The reaction mixture wasallowed to come to ambient temperature over a period of about 30 minutesand was then heated to refluxing temperature for an additional 30minutes. The precipitated material redissolved on heating.1-Dimethylamino-2-chloropropane hydrochloride began to crystallize fromthe boiling solvent. The reaction mixture was cooled, diluted with etherand filtered. The reaction product comprising1-dimethylamino-2-chloropropane hydrochloride weighed about 5.5 g. (95percent yield). Recrystallization yielded purified1-dimethylamino-2-chloropropane hydrochloride melting at 192°-194° C.

Two and two tenths grams of 1-dimethylamino-2-chloropropanehydrochloride were dissolved in an equal volume of water to which wasadded 1.5 ml. of 20 percent aqueous sodium hydroxide. The mixture wasthoroughly shaken. 1-Dimethylamino-2-chloropropane free base, beinginsoluble in the aqueous alkaline solution, separated and the separatedamine was extracted with two 5 ml. portions of ether. The ether layerswere combined and dried. Removal of the ether in vacuo yielded as anoily residue 0.8 g. of 1-dimethylamino-2-chloropropane.

A suspension of 1.36 g. (0.034 mol.) of finely ground sodium hydroxidewas prepared in 10 ml. of dried DMF. A solution containing 6.0 g. (0.031mol.) of diphenylacetonitrile in 8 ml. of DMF was added thereto at roomtemperature. After stirring the mixture for 15 minutes, 4.1 g. (0.034mol.) of 1-dimethylamino-2-chloropropane were added. The reactionmixture was heated with stirring to about 50° C. for about 1.5 hours andwas then cooled. The cooled reaction mixture was diluted with an equalvolume of water and the resulting suspension, containing a mixture of2,2-diphenyl-4-dimethylaminovaleronitrile and2,2-diphenyl-3-methyl-4-dimethylaminobutyronitrile formed in the abovereaction, was extracted with two 350 ml. portions of benzene. Thebenzene extracts were combined, washed with water and with saturatedsodium chloride solution and then dried. Removal of the solvent yieldedabout 7.83 g. of the crude reaction product which was shown by vaporphase chromatography to contain 58.4 percent, 2,2-diphenyl-4-dimethyl-aminovaleronitrile, 29.3 percent of2,2-diphenyl-3-methyl-4-dimethyl-aminobutyronitrile, and 10.8 percent ofstarting material diphenylacetonitrile. The methadone intermediateisomers were thus present in a ratio of 66.5: 33.5 Recrystallization ofthe crude reaction product from hexane yielded purified2,2-diphenyl-4-dimethylaminovaleronitrile which can be converted tomethadone by the procedure of Bockmuhl and Ehrhart, Ann., 561,52 (1948).In this procedure, the valeronitrile is reacted with ethyl magnesiumbromide to yield an intermediate imine which is hydrolized with base toyield the corresponding ketone.

The above reaction was also carried out employing DMSO in place of DMFas a solvent. The crude product analyzed for 60.6 percent of the desiredvaleronitrile isomer, 31.2 percent of the undesired methyl butyronitrileisomer, and 3.4 percent of unreacted diphenylacetonitrile (isomer ratio66:34).

EXAMPLE 2

A solution of 19.3 g. (0.1 mol.) of diphenylacetonitrile in 60 ml.dimethylformamide was added with stirring to a slurry of 8 g. (0.2 mol.)finely ground sodium hydroxide in 40 ml. dimethylformamide undernitrogen. The dark red color of the nitrile anion was observedimmediately. The mixture was heated to 75° ± 5° C. and 14.85 g. (0.12mol.) 1-dimethylamino-2-chloropropane were added at a rate such that thereaction temperature was maintained in the range 75°-80° C. withexternal cooling when necessary. The reaction mixture was stirred at 75°C. under nitrogen for 1 hour, cooled and diluted with 250 ml. water. Theaqueous mixture was extracted with 400 ml. of benzene in three portions.The extracts were combined and the combined extracts were washed withwater and with saturated sodium chloride solution, and were then driedover anhydrous sodium sulfate. Removal of the benzene at reducedpressure afforded 26.7 g. of the crude mixture of isomeric nitriles,shown by VPC analysis to contain 64.8 percent2,2-diphenyl-4-dimethylamino valeronitrile, 34.0 percent2,2-diphenyl-3-methyl-4-dimethylaminobutyronitrile, and 0.35 percentunreacted diphenylacetonitrile, the remainder of the material consistingof unidentified volatile impurities. The reaction was thus 99.6 percentcomplete. The ratio of isomeric nitriles was therefore, 65.6: 34.4 infavor of the desired valeronitrile methadone intermediate. The crudeproduct thus obtained was allowed to crystallize from hexane, affording12.6 g. (45 percent of theory based on diphenylacetonitrile) of2,2-diphenyl-4-dimethylaminovaleronitrile, mp 90°-91° C. having a purityof 99 percent by VPC analysis.

As previously stated, the produce of my novel process step is anintermediate in the synthesis of methadone. Methadone is not only auseful analgesic in its own right, but has recently proven to be ofconsiderable value in substituting for heroin in heroin addiction.Methadone substitution allows the usual heroin addict to lead a morenearly normal life even though an addiction to methadone is substitutedfor the addict's present heroin addiction.

I claim:
 1. In a process for preparing a mixture of2,2-diphenyl-4-dimethylaminovaleronitrile and2,2-diphenyl-3-methyl-4-dimethylaminobutyronitrile by the reaction ofdiphenylacetonitrile and 1-dimethylamino-2-chloropropane, theimprovement which consists in carrying out the reaction in an inertpolar, aprotic solvent having a dielectric constant greater than 28 at25° C. by forming the sodium salt of diphenylacetonitrile with sodiumhydroxide and then adding thereto 1-dimethylamino-2-chloropropane.
 2. Aprocess according to claim 1 in which the inert polar, aprotic solventis a member of the group consisting of N,N-dimethylformamide,N-methylformamide, di-methylsulfoxide and dimetjhylacetamide.
 3. Aprocess according to claim 1 in which the inert polar, aprotic solventis dimethylformamide.